The prevalence of impaired fecundity (>11%) and infertility (>6%) among women in the United States is considerable, and a significant proportion (>15%) of infertility remains unexplained by current scientific knowledge. The aim of this research is to further the understanding of the role that gene-environment interactions play in infertility. The deleterious effects of smoking on ovarian reserve and on in vitro fertilization procedures are evident, but more research needs to be done to understand the cumulative effects of lifetime exposure to smoking and to secondhand smoke on infertility. Exposure to tobacco smoke may be more harmful in patients who carry a particular slow-acetylator form of NAT2, a gene which plays an important role in metabolism of aromatic amines present in tobacco smoke. In this study, the effects of smoking alone, NAT2 alone, and their combined effects on ovarian reserve and in vitro fertilization (IVF) will be estimated. Past and current exposure to tobacco smoke will be determined by questionnaires and by assaying cotinine, a biomarker of smoking that will be measured in urine and follicular fluid. In Aim 1, the cumulative effect of lifelong exposure to active and passive smoking (secondhand smoke) on ovarian reserve and IVF success will be estimated. Ovarian reserve will be determined by measuring anti-Mllerian hormone levels and antral follicle count. Success of IVF will be determined by oocyte retrieval count, fertilization rate, and establishment of a clinical pregnancy. In Aim 2, patients will be tested to determine whether they carry the slow-acetylator form of the NAT2 gene, and it will be determined whether these individuals experience increased ovarian reserve or lower IVF success. Because NAT2 detoxifies aromatic and heterocyclic amines and is responsible for variability in the effect of arylamine and arylhydrazine drugs throughout the lifespan, the slow NAT2 phenotype may be associated with measures of ovarian reserve and IVF outcomes regardless of exposure to tobacco smoke. In Aim 3, the interaction between smoking and NAT2 on ovarian reserve and IVF success will be investigated. It is hypothesized that the effects of tobacco smoke exposure on these outcomes will be exacerbated among slow acetylators. Findings from this work will contribute to the understanding of infertility, especiall how environmental/behavioral risk factors and genetic susceptibility may interact to reduce a woman's fertility and shorten her reproductive lifespan.